The inhibitory receptor Programmed Death-1 (PD-1) has been shown to regulate CD8 T cell function during chronic SIV infection, however its role on CD4 T cells, specifically in the gut associated lymphoid tissue, is less well understood. Here, we show that a subset of CD4 T cells express high levels of PD-1 (PD-1hi) in the rectal mucosa, a preferential site of virus replication. The majority of these PD-1hi CD4 T cells expressed Bcl-6 and CXCR5, markers characteristic of T follicular helper cells in the lymph nodes. Following a pathogenic SIV infection, the frequency of PD-1hi cells (as a percent of CD4 T cells) dramatically increased in the rectal mucosa, however a significant fraction of them did not express CXCR5. Furthermore, only a small fraction of PD-1hi cells expressed CCR5 and despite this low level of viral co-receptor expression a significant fraction of these cells were productively infected. Interestingly, vaccinated SIV controllers did not present with this aberrant PD-1hi CD4 T cell enrichment and this lack of enrichment was associated with the presence of higher frequencies of SIV-specific granzyme B+ CD8 T cells within the lymphoid tissue, suggesting a role for anti-viral CD8 T cells in limiting aberrant expansion of PD-1hi CD4 T cells. These results highlight the importance of developing vaccines that enhance anti-viral CD8 T cells at sites of preferential viral replication and support the need for developing therapeutic interventions that limit expansion of SIV+ PD-1hi CD4 T cells at mucosal sites as a means to enhance viral control.

Cross-talk between B and T cells in transplantation is increasingly recognized as being important in the alloimmune response. T cell activation of B cells occurs by a 3-stage pathway, culminating with costimulation signals. We review the distinct T cell subtypes required for B cell activation, and discuss the formation of the Germinal Center (GC) after transplantation, with particular reference to the repopulation of the GC following depletional induction, and the subsequent effect of immunosuppressive manipulation of T-B cell interactions. Additionally, ectopic GCs are seen in transplantation, but their role is not fully understood. Therapeutic options to target T-B cell interactions are of considerable interest, both as immunosuppressive tools, and to aid further understanding of these important alloimmune mechanisms.